KR20060036572A - Process for the preparation of hydroxamate derivatives - Google Patents

Abstract

The present invention provides a novel method for preparing hydroxamate derivatives useful as intermediates in the preparation of intermediates or natural substances of fine chemicals used in pharmaceuticals and pesticides. It is a new method for preparing hydroxamate derivatives directly from carboxylic acid derivatives using a reaction method.

carboxylic acid, hydroxamate, hydroxylamine, triphosgene, triphenylphosphine                  

Description

 Process for the preparation of hydroxamate derivatives}

The present invention is a novel method for preparing a hydroxamate derivative represented by the general formula (I) useful as an intermediate in the intermediate of the fine chemicals used in pharmaceuticals and pesticides or in the presynthesis of natural substances, and the carboxylic acid of the general formula (II) The reaction of carboxylic acid derivatives with hydroxylamine derivatives in the presence of triphosgene and triphenylphosphine is a novel method for producing hydroxamate derivatives directly from carboxylic acid derivatives.

Wherein R represents hydrogen, an alkyl and substituted alkyl group having 1 to 20 carbon atoms, or an aryl and substituted aryl group, R ¹ represents hydrogen, R ² each independently represents hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl group.

The present invention is directed to a new method for obtaining hydroxamate derivatives directly from carboxylic acids which are generally known to be significantly less reactive. This method has the advantage that the whole synthesis process is simple and can be reacted at atmospheric pressure and mild conditions near room temperature, and also does not require the synthesis and separation of new intermediates, which are necessary for activating the carboxyl groups used in other synthesis methods. In addition, it aims to provide a new method for the synthesis of hydroxamate derivatives that are of high industrial value because little by-products are produced.

Several methods have been reported for the synthesis of hydroxamate derivatives as intermediates to synthesize useful compounds. Wu et al. In a paper published in 1991 in Tetrahedron Letters 32, 33, page 4137 obtained a hydroxamate derivative by reacting aldoxime with chloroformate in the presence of triethylsilane. In this reaction, the starting material aldoxime is not only a two-step reaction that must be obtained from the reaction of aldehyde and hydroxylamine, but also has a problem in that a product is obtained in low yield because it uses an unstable chloroformate derivative. Grierson et al. Obtained hydroxamate derivatives by introducing benzoyloxy groups into amines through the reaction of N- alkylamine and benzoyl peroxide in Tetrahedron Letters 34, 46, 1993. However, this reaction requires the handling of highly dangerous peroxides, which are explosive, requiring attention in the laboratory or in the industry. Abdelaziz et al. Obtained a hydroxamate derivative by reacting gem-dicyano epoxide with o -methylhydoroxylamine in a 1996 paper published on page 179 of Tetrahedron Letters 37, no.2. However, there is a disadvantage in that a product is obtained in a low yield because a high reaction temperature is required to obtain a product from this reaction and also a byproduct is produced. Giacomelli et al. Obtained an intermediate in which a carboxylic acid derivative was activated using 2-chloro-4,6-dimethoxy- [1,3,5] triazine in a 2001 paper published in Journal of Organic Chemistry, Vol. 66, page 2534. The target compound was obtained from the two-step reaction of reacting this with hydroxylamine derivative to obtain a hydroxamate derivative. Fray et al., 2001, Bioorganic & Medicinal Chemistry Letters, Vol. 11, page 567, used to react carboxylic acid derivatives and hydroxylamine derivatives in N, N- dimethylformamide solvents using EDC and HOBt. In this case, there is a problem that the reaction time is long and the product is obtained in a low yield. Sibi et al. Synthesized hydroxamate derivatives by reacting N- acyloxazolidinone derivatives with hydroxylamine derivatives in the presence of Lewis acid such as samarium triflate in 2002, Organic Letters Vol. . Devocelle et al., 2003, Org. Biomol. Chem. In a paper published on Volume 1, page 850, hydroxamate derivatives were synthesized by carboxylic acid as an active ester using a 1-hydroxybenzotriazol conjugated with a polymeric material and then reacted with a hydoroxylamine derivative. However, this reaction proceeds in two stages, which requires heating at a high reaction temperature for a long time and has a problem in that a product is obtained in a low yield.

As described above, a method of synthesizing a hydroxamate derivative directly from a known carboxylic acid derivative may be performed by synthesizing another intermediate under violent conditions to react with a hydroxylamine derivative or to increase the reactivity of the carboxyl group. After synthesis of carboxylic acid-activated intermediates, hydroxamate derivatives were synthesized by reacting with hydroxylamine derivatives. However, these conventional synthesis methods have a problem of effectively separating the by-products generated with the desired product, and because of the multi-step reaction, there is a limitation in industrial use such as a long manufacturing process and a low overall yield. Undesirable methods. The present inventors have made efforts to establish a preferable method while paying attention to the above problems, and as a result, a simple one-stage reaction is performed by reacting the carboxylic acid derivative directly with the hydroxylamine derivative in a short time under mild conditions near normal pressure and room temperature. The present invention was completed by developing a new method for synthesizing hydroxamate derivatives without formation.

The present invention is a novel method for preparing a hydroxamate derivative represented by the general formula (I) useful as an intermediate in the intermediate of the fine chemicals used in pharmaceuticals and pesticides or in the presynthesis of natural substances, and the carboxylic acid of the general formula (II) The reaction of carboxylic acid derivatives with hydroxylamine derivatives in the presence of triphosgene and triphenylphosphine is a new method for the direct preparation of hydroxamate derivatives from carboxylic acid derivatives without any unnecessary intermediate separation.

Wherein R represents hydrogen, an alkyl and substituted alkyl group having 1 to 20 carbon atoms, or an aryl and substituted aryl group, R ¹ represents hydrogen, and R ² independently represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl group .

Triphosgene and triphenylphosphine used in the present invention activates a less reactive carboxyl group, and triphosgene uses 0.50 to 1.00 mole times compared to the carboxylic acid derivative of general formula (II) and triphenylphosphine is a carbohydrate of general formula (II) 1.0 mole to 1.2 mole times relative to the acid derivative is used. The hydroxylamine derivative can be used both hydroxylamine and o- protected hydroxylamine, 1.0 to 2.0 mole times, preferably 1.0 to 1.2 mole times compared to the carboxylic acid derivative of the general formula (II). A tertiary amine, such as triethylamine, is used to neutralize HCl generated on the presumed mechanism, and the reaction temperature range is from 0 to 45 ^° C., preferably from 0 to 25 ^° C. As the reaction solvent, all common organic solvents such as chloroform, dichloromethane and toluene can be used. Referring to the reaction sequence constituting the present invention is as follows.

After adding triphosgene and triphenylphosphine to dichloromethane at 0 to 5 ^o C for 5 minutes to form PPh ₃ Cl ₂ , the carboxylic acid derivative and triethylamine of formula (II) are added and stirred to increase the reactivity of the carboxyl group. Acid chloride form intermediates are formed. Then, the hydroxylamine derivative is added and the reaction mixture is stirred while naturally warming to room temperature to obtain the desired hydroxamate derivative of the general formula (I) through the transfer and reconstitution of the bonding electrons.

In the present invention, the triphosgene used as an activating reagent for carboxylic acid is used as a cyclic carbonate synthesis reagent from 1,3-cyclic diol or Burqi et al., Published on page 395 of Tetrahedron Letters 34, No. 3, 1993. J. Organometallic Chem. It was used as a reagent for the production of ferrocenoyl chloride from ferrocene carboxylic acid, as published on vol. 604, p. 287. As a reagent mainly used for the reaction, a reagent for synthesizing an ester derivative by activating a carboxylic acid was first identified and developed by the present inventors. Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to the methods presented in the Examples.

Example 1.

15 mL of dichloromethane was added to a 30 mL flask under nitrogen atmosphere, cooled to 0-5 ^° C in an ice bath, 524 mg (2.0 mmole) of triphenylphosphine and 296 mg (1.0 mmole) of triphosgene were added and stirred for 5 minutes. 314 mg (2.0 mmole) of 3-chlorobenzoic acid and 607 mg (6.0 mmole) of triethylamine were added thereto and stirred for 20 minutes. After adding 166 mg (2.0 mmole) of O -methylhydroxylamine hydrochloride, the ice-bath was removed and the mixture was cooled to room temperature. After stirring for 1 hour, the reaction was confirmed that the acid was completely converted to hydroxamate by TLC. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 362 mg of a hydroxamate derivative as a target compound (yield 97.2%).

Example 2

15 mL of dichloromethane was added to a 30 mL flask under nitrogen atmosphere, cooled to 0-5 ^° C in an ice bath, 524 mg (2.0 mmole) of triphenylphosphine and 296 mg (1.0 mmole) of triphosgene were added and stirred for 5 minutes. 244 mg (2.0 mmole) of benzoic acid and 607 mg (6.0 mmole) of triethylamine were added thereto and stirred for 20 minutes. After adding 194 mg (2.0 mmole) of O -ethylhydroxylamine hydrochloride, the ice-bath was removed and the temperature was raised to room temperature. After stirring and reacting for about 1 hour, TLC showed that the acid was completely converted into hydroxamate. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 313 mg of a hydroxamate derivative as a target compound (yield 94.8%).

Example 3

15 mL of dichloromethane was added to a 30 mL flask under nitrogen atmosphere, cooled to 0-5 ^° C in an ice bath, 524 mg (2.0 mmole) of triphenylphosphine and 296 mg (1.0 mmole) of triphosgene were added and stirred for 5 minutes. 272 mg (2.0 mmole) of 4-toluic acid and 607 mg (6.0 mmole) of triethylamine were added thereto, stirred for 20 minutes, and then 166 mg (2.0 mmole) of O -methylhydroxylamine hydrochloride was added. After stirring for 1 hour, the reaction was confirmed that the acid was completely converted to hydroxamate by TLC. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 310 mg of a hydroxamate derivative as a target compound (yield 93.8%).

Example 4

15 mL of dichloromethane was added to a 30 mL flask under nitrogen atmosphere, cooled to 0-5 ^° C in an ice bath, 524 mg (2.0 mmole) of triphenylphosphine and 296 mg (1.0 mmole) of triphosgene were added and stirred for 5 minutes. 296 mg (2.0 mmole) of trans- cinnamic acid and 607 mg (6.0 mmole) of triethylamine were added thereto, stirred for 20 minutes, and 319 mg (2.0 mmole) of O- benzylhydroxylamine hydrochloride was added. After stirring for 1 hour, the reaction was confirmed that the acid was completely converted to hydroxamate by TLC. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 474 mg of a hydroxamate derivative as a target compound (yield 93.7%).

Example 5

15 mL of dichloromethane was added to a 30 mL flask under nitrogen atmosphere, cooled to 0-5 ^° C in an ice bath, 524 mg (2.0 mmole) of triphenylphosphine and 296 mg (1.0 mmole) of triphosgene were added and stirred for 5 minutes. 244 mg (2.0 mmole) of benzoic acid and 607 mg (6.0 mmole) of triethylamine were added thereto and stirred for 20 minutes. Then, 218 mg (2.0 mmole) of O -allylhydroxylamine hydrochloride was added and the ice-bath was removed. After stirring and reacting for about 1 hour, TLC showed that the acid was completely converted into hydroxamate. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 336 mg of a hydroxamate derivative as a target compound (yield 95.0%).

 Example 6

15 mL of dichloromethane was added to a 30 mL flask under nitrogen atmosphere, cooled to 0-5 ^° C in an ice bath, 524 mg (2.0 mmole) of triphenylphosphine and 296 mg (1.0 mmole) of triphosgene were added and stirred for 5 minutes. 246 mg (2.0 mmole) of nicotinic acid and 607 mg (6.0 mmole) of triethylamine were added thereto and stirred for 20 minutes. Then, 194 mg (2.0 mmole) of O -ethylhydroxylamine hydrochloride was added and the ice-bath was removed. After stirring and reacting for about 1 hour, TLC showed that the acid was completely converted into hydroxamate. Triethylamine hydrochloride produced as a solid was removed by filtration through a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 301 mg of a hydroxamate derivative as a target compound (yield 92.3%).

Other known methods of synthesizing hydroxamate derivatives directly from carboxylic acid derivatives are known to synthesize another intermediate under vigorous conditions to activate a less reactive carboxyl group and react with hydroxylamine derivatives or to increase the reactivity of the carboxyl group. After synthesizing the intermediate with acid, the intermediate was reacted with hydroxylamine derivative to synthesize hydroxamate derivative. However, these conventional synthesis methods have a problem of effectively separating the by-products generated with the desired product, and because of the multi-step reaction, there is a limitation in industrial use such as a long manufacturing process and a low overall yield. It was an undesirable method. In contrast, the present invention can proceed like a simple one-step reaction, not a multi-step reaction, and can react hydrocarboxylic acid derivatives without generating by-products by directly reacting carboxylic acid derivatives with hydroxylamine derivatives in a short time under mild conditions near atmospheric pressure and room temperature. It's a new way. Therefore, the whole synthesis process is simple and can complete the reaction in a short time, and it is a synthesis method of a new hydroxamate derivative that generates little by-products, and it is a synthesis process with excellent reliability and reproducibility of reaction. In contrast, the process of separating and refining the target compound is easy, without causing any environmental problems, which will greatly contribute to economic efficiency.

Claims (3)

A method for producing a hydroxamate derivative of the general formula (I), characterized by reacting a carboxylic acid derivative of the general formula (II) with a hydroxylamine derivative in the presence of triphosgene and triphenylphosphine.

Wherein R represents hydrogen, an alkyl and substituted alkyl group having 1 to 20 carbon atoms, or an aryl and substituted aryl group, R ¹ represents hydrogen, R ² each independently represents hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl group. The method for preparing a hydroxamate derivative of formula (I) according to claim 1, wherein the triphosgene is reacted in the presence of triphenylphosphine using 0.50 to 1.00 mol times of the carboxylic acid derivative of formula (II). The method for producing a hydroxamate derivative of general formula (I) according to claim 1, wherein the reaction temperature is 0 to 45 ^° C.